Fibrosis of cells that brings about functional disorders of various organs and tissue is a great clinical problem in the alleviation of inflammation and the curing of wounds in organs or tissue. In joints, fibrosis of cells causes articular rheumatism, and in the liver, progress of cellular fibrosis leads to hepatic cirrhosis, causing jaundice and hypoproteinemia and eventually leading to liver failure. In blood vessels, fibrosis of vascular walls causes loss of elasticity of the walls, leading to arteriosclerosis. The first step of fibrosis is granulation, and therefore, it is considered that articular rheumatism,-hepatic cirrhosis, arteriosclerosis, etc. would be successfully treated if granulation could be inhibited.
In the development of pharmaceuticals, compounds having liver toxicity are problematic for successful development. In Nature No. 283, 397-398 (1980), it is reported that increased production of peroxisome, which causes hepatomegaly, is a carcinogenetic factor.
Therefore, there is strong demand for pharmaceuticals which exhibit excellent granulation inhibiting activity with minimal liver toxicity and which are thus advantageously used in clinical situations.
Analogs of a 3-(bis-substituted phenylmethylene)-oxindole derivative, which is the compound of the present invention, are disclosed in Ber., 96 (1963), 3328-37, Japanese Patent Publication (kokoku) No. 43-3195, and in U.S. Pat. No. 3,428,649. Of the analogs, 3-[bisphenylmethylene]-oxindole (compound a) of the following formula, disclosed in Ber., 96 (1963), 3328-37 is particularly close to the compounds of the present invention. However, that compound is merely disclosed as a synthesis intermediate, and no pharmacological activity is described at all. ##STR2##
Japanese Patent Publication (kokoku) No. 43-3195 discloses, as a synthesis intermediate, an oxindole derivative represented by the following formula (2): ##STR3## (wherein each of R.sup.1 and R.sup.2 represents lower alkyl, aryl, or pyridyl; and R.sup.3 represents a hydrogen atom or lower alkyl).
However, the disclosure of 3-(bis-substituted phenylmethylene)oxindole derivative in that publication is in fact directed only to specific compounds in which R.sup.3 is a methyl group and R.sup.1 and R.sup.2 are both unsubstituted phenyl groups, and to use as synthesis intermediates.
Accordingly, the object of the present invention is to provide a novel oxindole derivative which exhibits excellent granulation inhibiting activity while providing minimal liver toxicity and which is thus advantageously used as a pharmaceutical.